Persistent leukocytosis in polycythemia vera is associated with disease evolution but not thrombosis.

There are unresolved questions regarding the association between persistent leukocytosis and risk of thrombosis and disease evolution in polycythemia vera (PV), as much of the published literature on the topic does not appropriately use repeated-measures data or time-dependent modeling to answer these questions. To address this knowledge gap, we analyzed a retrospective database of 520 PV patients seen at 10 academic institutions across the United States. Taking hematologic laboratory data at ∼3-month intervals (or as available) for all patients for duration of follow-up, we used group-based trajectory modeling to identify latent clusters of patients who follow distinct trajectories with regard to their leukocyte, hematocrit, and platelet counts over time. We then tested the association between trajectory membership and hazard of 2 major outcomes: thrombosis and disease evolution to myelofibrosis, myelodysplastic syndrome, or acute myeloid leukemia. Controlling for relevant covariates, we found that persistently elevated leukocyte trajectories were not associated with the hazard of a thrombotic event (P = .4163), but were significantly associated with increased hazard of disease evolution in an ascending stepwise manner (overall P = .0002). In addition, we found that neither hematocrit nor platelet count was significantly associated with the hazard of thrombosis or disease evolution.

Ruxolitinib Re-Treatment in Patients with Myelofibrosis: Real-World Evidence on Patient Characteristics and Outcomes.

Ruxolitinib is an FDA-approved treatment of intermediate- and high-risk myelofibrosis. In the phase 3 COMFORT studies, ruxolitinib reduced spleen volume in patients with myelofibrosis, with a median time to response of 3 months. However, nearly 20% of patients discontinued by month 4 with few treatment options available following discontinuation of ruxolitinib treatment. In this study, 2 independent patient care data sources were queried (Cardinal Health Oncology Provider Extended Network [OPEN] and HealthCore Integrated Research Environment [HIRE®]), and a retrospective review of medical charts was conducted. Patients aged ≥18 years with a diagnosis of myelofibrosis (primary or secondary), use of ruxolitinib for myelofibrosis, and documented physician-directed ruxolitinib interruption were included. Among 26 included patients, pre-interruption median (interquartile range [IQR]) ruxolitinib treatment duration was 123 (57-391, OPEN) and 110 (37-148, HIRE) days. Half the patients interrupted treatment within 3 months, commonly for adverse events (42% and 71%, respectively). After restarting ruxolitinib, median (IQR) re-treatment duration was 196 (54-553) and 166 (108-262) days, respectively. Consistent with previous reports, symptoms and spleen size improved in (OPEN/HIRE) 45%/43% and 40%/33% of evaluable patients, respectively. Further studies investigating the management of dose modifications and interruptions are needed to optimize benefit from ruxolitinib therapy.

Tobacco use in the Myeloproliferative neoplasms: symptom burden, patient opinions, and care.

BACKGROUND: Patients with Philadelphia-negative Myeloproliferative Neoplasms (MPN) suffer from numerous symptoms and decreased quality of life. Smoking is associated with an increased symptom burden in several malignancies. The aim of this study was to analyze the association between smoking and MPN-related symptom burden and explore MPN patients' opinions on smoking. METHODS: A total of 435 patients with MPN participated in a cross-sectional internet-based survey developed by the Mayo Clinic and the Myeloproliferative Neoplasm Quality of Life Group. Patients reported their demographics, disease characteristics, tobacco use, and opinions on tobacco use. In addition, MPN-related symptoms were reported via the validated 10-item version of the Myeloproliferative Neoplasms Symptom Assessment Form. RESULTS: Current/former smokers reported worse fatigue (mean severity 5.6 vs. 5.0, p = 0.02) and inactivity (mean severity 4.0 vs. 3.4, p = 0.03) than never smokers. Moreover, current/former smokers more frequently experienced early satiety (68.5% vs. 58.3%, p = 0.03), inactivity (79.9% vs. 71.1%, p = 0.04), and concentration difficulties (82.1% vs. 73.1%, p = 0.04). Although not significant, a higher total symptom burden was observed for current/former smokers (mean 30.4 vs. 27.0, p = 0.07). Accordingly, overall quality of life was significantly better among never smokers than current/former smokers (mean 3.5 vs. 3.9, p = 0.03). Only 43.2% of the current/former smokers reported having discussed tobacco use with their physician, and 17.5% did not believe smoking increased the risk of thrombosis. CONCLUSION: The current study suggests that smoking may be associated with increased prevalence and severity of MPN symptoms and underscores the need to enhance patient education and address tobacco use in the care of MPN patients.

Assessment of Quality of Life following Allogeneic Stem Cell Transplant for Myelofibrosis.

Patient-reported outcomes (PROs) for patients with myelofibrosis (MF) have been well characterized, but little is known about quality of life (QoL) following allogeneic stem cell transplantation (allo-SCT). Medical data and PRO measures were collected before transplant and at day 30, day 100, and 1 year after allo-SCT. PRO measures include Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), Brief Fatigue Inventory, Global Assessment of Change, and Functional Assessment of Cancer Therapy-Bone Marrow Transplant. Forty-four patients who had baseline QoL and at least 1 post-transplant assessment were included. The median age of the patients was 62.5 years (range, 35 to 74 years). At baseline, the mean MPN Total Symptom Score was 28.0, and at day 30, day 100, and 1 year, it was 25.4, 32.3, and 24.3, respectively. However, in myeloproliferative neoplasm-specific symptoms, such as itching, night sweats, bone pain, and fever, a statistically significant improvement was observed for at least 1 time point following transplant. At day 30, 10 (26.3%) patients reported a little/moderately/very much better overall QoL since their transplant, and 26 (68.45%) had a little/moderately/very much worse QoL. At day 100, 10 (30.3%) reported better QoL and 19 (57.6%) reported worsening since transplant. By 1 year, 16 (61.5%) reported feeling better. Our study shows that there is very little change in symptom burden at 1 year following transplant in general, but MF-specific symptoms showed improvement. By 1 year, 61% felt that their QoL was better than it was before transplant.

How we diagnose and treat systemic mastocytosis in adults.

Rapid advances in the understanding of the molecular biology, data from translational and clinical trials, and retrospective analyses has influenced the diagnosis and treatment of systemic mastocytosis (SM). Many options have existed for the symptomatic management of SM patients, but recent evolution in regards to the molecular underpinnings of this disease and our ability to distinguish clonal mastocytosis from mast cell activation syndrome has changed our treatment paradigm and opened new opportunities for understanding genetic risk, transformation to mast cell leukaemia, and treatment choices. Key to this change has been the discovery of the KIT mutation and the use of next generation sequencing to evaluate for co-existing molecular mutations that may define the disease course. Careful diagnosis, judicious symptom management and close surveillance of those who may have yet undiagnosed disease is paramount in providing optimal management. In this article, we review the diagnosis and provide a paradigm for the management of SM patients.

Precision immunotherapy, mutational landscape, and emerging tools to optimize clinical outcomes in patients with classical myeloproliferative neoplasms.

Following the 47th American Society of Hematology Meeting in 2005, the late John Goldman and Tariq Mughal commenced a conference, the 1st Post-ASH Workshop, which brought together clinicians and scientists, to accelerate the adoption of new therapies for patients with myeloproliferative neoplasms (MPNs). The concept began with recognition of the CML success story following imatinib therapy, the discovery of JAK2V617F , and the demonstration that BCR-ABL1-negative MPNs are driven by abnormal JAK2 activation. This review is based on the presentations and deliberations at the XIIth Post-ASH Workshop on BCR-ABL1 positive and negative MPNs that took place on December 12 to 13, 2017, in Atlanta, Georgia, immediately following the 59th American Society of Hematology Meeting. We have selected some of the translational research and clinical topics, rather than an account of the proceedings. We discuss the role of immunotherapy in MPNs and the impact of the mutational landscape on TKI treatment in CML. We also consider how we might reduce TKI cardiovascular side effects, the potential role of nutrition as adjunctive nonpharmacologic intervention to reduce chronic inflammation in MPNs, and novel investigational therapies for MPNs.

Comprehensively understanding fatigue in patients with myeloproliferative neoplasms.

BACKGROUND: Patients with myeloproliferative neoplasms (MPNs) experience a high persistence, prevalence, and severity of fatigue. There is currently only limited information regarding factors that contribute to fatigue in patients with MPNs. METHODS: A 70-item, Internet-based survey regarding fatigue was developed by MPN investigators and patients/advocates and hosted by the Mayo Clinic Survey Research Center. RESULTS: Fatigue was found to be prevalent and severe among international survey respondents (1788 respondents). Higher body mass index (P<.001), current use of alcohol (P<.001), and current tobacco use (P = .0025) were found to be significantly associated with greater fatigue. Moderate/severe fatigue was present more frequently in those individuals who did not exercise compared with those who reported exercising at least once per week (P<.001). Medical comorbidities found to be significantly associated with greater fatigue included restless leg syndrome (P = .006), diabetes mellitus (P = .045), fibromyalgia (P < 0.001), chronic fatigue syndrome (P = .006), and chronic kidney disease (P = .02). Current use of antidepressants (P<.001), antihistamines (P = .0276), antianxiety medications (P = .0357), and prescription pain medications (P<.001) were found to be associated with worsened fatigue. Nearly 25% of respondents scored > 2 on the Patient Health Questionnaire, indicating a high probability of depression. Higher Brief Fatigue Inventory score, Myeloproliferative Neoplasm Total Symptom Score, and individual symptom items were all associated with a higher likelihood of depressive symptoms (P<.0001). CONCLUSIONS: The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. Patients with MPNs likely have a higher prevalence of mood disturbances compared with the general population, suggesting the need to assess and intervene in this domain.

The role of sexuality symptoms in myeloproliferative neoplasm symptom burden and quality of life: An analysis by the MPN QOL International Study Group.

BACKGROUND: Patients with myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and myelofibrosis, are faced with oppressive symptom profiles that compromise daily functioning and quality of life. Among these symptoms, sexuality-related symptoms have emerged as particularly prominent and largely unaddressed. In the current study, the authors evaluated how sexuality symptoms from MPN relate to other patient characteristics, disease features, treatments, and symptoms. METHODS: A total of 1971 patients with MPN (827 with essential thrombocythemia, 682 with polycythemia vera, 456 with myelofibrosis, and 6 classified as other) were prospectively evaluated and patient responses to the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ C30) were collected, along with information regarding individual disease characteristics and laboratory data. Sexuality scores were compared with an age-matched, healthy control population. RESULTS: Overall, patients with MPN were found to have greater sexual dysfunction compared with the healthy population (MPN-SAF score of 3.6 vs 2.0; P<.001), with 64% of patients with MPN describing some degree of sexual dysfunction and 43% experiencing severe symptoms. The presence of sexual symptoms correlated closely with all domains of patient functionality (physical, social, cognitive, emotional, and role functioning) and were associated with a reduced quality of life. Sexual problems also were found to be associated with other MPN symptoms, particularly depression and nocturnal and microvascular-related symptoms. Sexual dysfunction was more severe in patients aged >65 years and in those with cytopenias and transfusion requirements, and those receiving certain therapies such as immunomodulators or steroids. CONCLUSIONS: The results of the current study identify the topic of sexuality as a prominent issue for the MPN population, and this area would appear to benefit from additional investigation and management. Cancer 2016;122:1888-96. © 2016 American Cancer Society.

Distinct clustering of symptomatic burden among myeloproliferative neoplasm patients: retrospective assessment in 1470 patients.

Symptom burden in myeloproliferative neoplasms (MPNs) is heterogeneous even among patients within the same MPN diagnosis. Using cluster analysis from prospectively gathered symptom burden data in 1470 international patients with essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF), we assessed for the presence of clusters and relationship to disease features and prognosis. In MF (4 clusters identified), clusters significantly differed by Dynamic International Prognostic Scoring System (DIPSS) risk (P < .001), leukopenia (P = .009), thrombocytopenia (P < .001), and spleen size (P = .02). Although an association existed between clusters and DIPSS risk, high symptom burden was noted in some low and intermediate-1-risk MF patients. In PV (5 clusters identified), total symptom score increased across clusters (P < .001), but clusters did not significantly differ by PV risk or the risk assessment variable of age. Among ET patients (5 clusters identified), clusters differed by gender (P = .04), anemia (P = .01), and prior hemorrhage (P = .047). Total symptom score increased across clusters (P < .001), but clusters did not significantly differ by International Prognostic Score for ET risk including the risk assessment variables. Significant symptom heterogeneity exists within each MPN subtype, sometimes independent of disease features or prognosis.

Impact of Inflammation on Myeloproliferative Neoplasm Symptom Development.

Myeloproliferative neoplasms (essential thrombocythemia, ET; polycythemia vera, PV; myelofibrosis, MF) are monoclonal malignancies associated with genomic instability, dysregulated signaling pathways, and subsequent overproduction of inflammatory markers. Acknowledged for their debilitating symptom profiles, recent investigations have aimed to determine the identity of these markers, the upstream sources stimulating their development, their prevalence within the MPN population, and the role they play in symptom development. Creation of dedicated Patient Reported Outcome (PRO) tools, in combination with expanded access to cytokine analysis technology, has resulted in a surge of investigations evaluating the potential associations between symptoms and inflammation. Emerging data demonstrates clear relationships between individual MPN symptoms (fatigue, abdominal complaints, microvascular symptoms, and constitutional symptoms) and cytokines, particularly IL-1, IL-6, IL-8, and TNF-α. Information is also compiling on the role symptoms paradoxically play in the development of cytokines, as in the case of fatigue-driven sedentary lifestyles. In this paper, we explore the symptoms inherent to the MPN disorders and the potential role inflammation plays in their development.

The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Results from a Randomized Phase I Pilot Study for Feasibility and Adherence.

PURPOSE: Chronic inflammation is integral to myeloproliferative neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among patients with MPN. EXPERIMENTAL DESIGN: We randomly assigned patients with MPN to either a Mediterranean diet or standard U.S. Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four timepoints during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome. RESULTS: The Mediterranean diet was as easy to follow for patients with MPN as the standard USDA diet. Approximately 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any timepoint. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention. CONCLUSIONS: With dietician counseling and written education, patients with MPN can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially incorporated into the management of other hematologic conditions. SIGNIFICANCE: Diet is a central tenant of management of chronic conditions characterized by subclinical inflammation, such as cardiovascular disease, but has not entered the treatment algorithm for clonal hematologic disorders. Here, we establish that a Mediterranean diet intervention is feasible in the MPN patient population and can improve symptom burden. These findings warrant large dietary interventions in patients with hematologic disorders to test the impact of diet on clinical outcomes.

The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Feasibility Phase.

Purpose: Chronic inflammation is integral to Myeloproliferative Neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among MPN patients. Experimental Design: We randomly assigned participants to either a Mediterranean diet or standard US Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four time points during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome. Results: The Mediterranean diet was as easy to follow for MPN patients as the standard USDA diet. Over 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any time point. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention. Conclusions: With dietician counseling and written education MPN patients can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially even be incorporated into the management of other chronic clonal hematologic conditions.

Changes in the incidence and overall survival of patients with myeloproliferative neoplasms between 2002 and 2016 in the United States.

This analysis examined trends in incidence and survival among US adults with myeloproliferative neoplasms, including essential thrombocythemia (ET; n = 14,676), polycythemia vera (PV; n = 15,141), and primary myelofibrosis (PMF; n = 4214), using Surveillance, Epidemiology, and End User Results (SEER) data (SEER 18; 2002-2016). Incidence and survival rates over the study period and by diagnosis year (per 5-year time frames: 2002-2006; 2007-2011; 2012-2016) were assessed. The overall incidence rates (95% CI) were 1.55 (1.52-1.57) for ET, 1.57 (1.55-1.60) for PV, and 0.44 (0.43-0.45) per 100,000 person-years for PMF, with rising ET incidence. Five-year mortality over the study period was 19.2%, 19.0%, and 51.0% for ET, PV, and PMF, respectively. Improved survival over time was observed for PV and PMF, but not for ET. These findings highlight the need for effective ET therapies, as ET incidence has risen without concurrent improvements in survival over the past 2 decades.

Thrombotic events and mortality risk in patients with newly diagnosed polycythemia vera or essential thrombocythemia.

Patients with polycythemia vera (PV) and essential thrombocythemia (ET) have increased thrombotic risk. This retrospective, real-world analysis of Medicare patients (age ≥ 65 years) newly diagnosed with high-risk PV or intermediate-/high-risk ET compared mortality risk among those with versus without thrombotic events during the study period. Patients diagnosed with PV or ET with ≥ 1 inpatient or ≥ 2 outpatient claims (January 1, 2010-December 31, 2017; index was date of first qualifying claim) were included. The study included 50,405 Medicare beneficiaries with PV and 124,569 with ET. During follow-up (median [range]: PV, 34.5 [0-97.3] months; ET, 25.5 [0-97.4] months), 14,334 patients (28.4%) with PV and 30,478 (24.5%) with ET experienced thrombotic events (most commonly ischemic stroke [PV, 46.0%; ET, 42.5%]. Mortality risk was increased for patients with versus without post-index thrombosis for both PV (adjusted hazard ratio [aHR; 95% CI], 18.6 [16.1-21.6]; P < 0.001) and ET (aHR [95% CI], 25.2 [23.1-27.5]; P < 0.001). Median survival was shorter for patients who experienced a thrombotic event ≤ 1 year post-index versus those who did not (PV, 5.1 years vs not reached; ET, 3.7 vs 6.7 years; both P < 0.001). These findings highlight the importance of thrombosis risk mitigation in PV and ET management.

Assessing Symptom Burden in Myelodysplastic Syndrome/Myeloproliferative Neoplasm Overlap Patients.

Myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes are rare types of chronic myeloid hematologic neoplasms. Patients with overlap syndrome have similar clinical features, mutations, and disease course, to other chronic myeloid malignancies. Limited data also suggests that overlap syndromes patients experience long standing and at times poorly controlled symptoms that may be underrecognized. In this article, we discuss the etiologies of symptoms in patients with overlap syndromes and currently available symptom burden assessment tools. Overall, symptom burden is an important consideration in patients with overlap syndrome, and efforts are ongoing to further investigate symptom burden and quality of life in this population.

Management of challenging myelofibrosis after JAK inhibitor failure and/or progression.

The myeloproliferative neoplasms (MPNs) encompass a heterogenous set of diseases that have variable survival, but in the setting of treatment refractory and progressive disease, prognosis has been characteristically poor. JAK inhibition with ruxolitinib or fedratinib therapy has become the first line treatment for symptomatic or intermediate to high risk myelofibrosis. However, after three years of ruxolitinib therapy, approximately half of all patients with myelofibrosis will likely have stopped treatment. JAK inhibition failure represents a mixture of etiologies, including drug intolerance, suboptimal dosing, drug resistance, or progression of disease. JAK inhibition failure and accelerated/blast phase have now become the primary clinical challenges in the treatment of myelofibrosis and high risk polycythemia vera, and no phase III trials or clear treatment guidelines exist to guide management strategies in this setting. On the other hand, this represents an exciting time in treatment of JAK inhibitor failure and accelerated phase MPNs due to the advent of recently approved drugs as well as new targeted agents currently under investigation. In this article, we review the management options for these challenging clinical scenarios. We discuss the options for JAK inhibitor dose optimization and overcoming resistance by utilizing combinations of JAK inhibition, primarily ruxolitinib, with alternative commercially available therapies. For patients who have progressed, we discuss recent data regarding targeted therapy options approved for AML that represent potentially efficacious options in the progressive MPN setting. We also discuss the new clinical agents under development in MF and accelerated MPNs that may offer new therapeutic options in the years to come.

Support needs of overweight African American women for weight loss.

OBJECTIVES: To examine social support needs of obese and overweight African American women for weight loss. METHODS: Focus groups were conducted with overweight and obese African American women. Data were analyzed using standard grounded theory text analysis. RESULTS: Our middle-aged (45.7 years; SD = 12.6) women (N = 66) were interested in receiving support from others focused on the health benefits of weight loss. Behaviors perceived as supportive include co-participating in exercise, providing nutrition education, using positive reinforcements, and avoiding criticism. CONCLUSIONS: African American women are interested in a program designed to increase social support for their weight loss.